Critical illness of burns or sepsis and neuronal injuries are associated with muscle weakness. The pathognomic biochemical feature observed in all the conditions is an upregulation (increase) of acetylcholine receptors (AChRs) with de novo expression of immature isoform of AChRs. The common morphologic feature is the loss of muscle mass. The long term objectives and focus of the present proposal, using the rat model, are to characterize the etiology of the functional impairment (muscle weakness) associated with burn injury, whether it is synaptic (due to expression if immature AChRs) or postsynaptic (due to apoptosis) in origin, and to identify the compounding effects of immobilization. and of muscle relaxants in the neuromuscular dysfunction of burns. It is hypothesized that the pathophysiological bases for the expression of the immature isoform of AChRs and the loss of muscle mass are due to a loss of growth factor signaling (a) of AGRIN via muscle specific kinase (MuSK) which plays an important role in clustering, expression and maturation of AchRs and (b) via phosphotidylinositol 3- kinase (PI 3-K), a key anti-apoptotic factor which can be activated by IGF-1. A 40 percent body surface area burn to the flank of approximately 5 percent local burn to the lower leg and examination of the neuromuscular changes in the lower limb would characterize the distant and local effects of the burn. The compounding effects of simple immobilization (by pinning of joints) or of muscle relaxants (administered directly to the leg to avoid total body paralysis) will be studied alone and in combination with the burn. The experimental protocol includes the measurement of contractility, fatiguability, fiber type change in fast twitch, tibialis and slow twitch, soleus. Changes in function with and without AGRIN will be correlated with MuSK expression/phosphorylation and to expression of immature AChRs. Apoptosis associated with these perturbations will be studied in local and distant sites by in situ TUNEL and DNA fragmentation ladder assays. The expression of pro and anti-apoptotic factors with and without IGF-1 will indicate the potential pathways that are activated or deactivated, and the utility of IGF-1 in the prevention of apoptosis. These studies, therefore, will provide information on the functional and biochemical alterations in the neuromuscular apparatus following burns, immobilization and.or muscle relaxant therapy, insight into the etiology of muscle weakness, and also provide a rational scientific basis for the administration of appropriate therapeutic agents to rectify the neuromuscular changes.